Abstract

The cellular and molecular mechanisms underpinning the compensatory increase in β-cell mass in response to insulin resistance
are essentially unknown. We previously reported that a 72-h coinfusion of glucose and Intralipid (GLU+IL) induces insulin
resistance and a marked increase in β-cell proliferation in 6-month-old, but not in 2-month-old, Wistar rats. The aim of the
current study was to identify the mechanisms underlying nutrient-induced β-cell proliferation in this model. A transcriptomic
analysis identified a central role for the forkhead transcription factor FOXM1 and its targets, and for heparin-binding epidermal
growth factor (EGF)-like growth factor (HB-EGF), a ligand of the EGF receptor (EGFR), in nutrient-induced β-cell proliferation.
Phosphorylation of ribosomal S6 kinase, a mammalian target of rapamycin (mTOR) target, was increased in islets from GLU+IL–infused
6-month-old rats. HB-EGF induced proliferation of insulin-secreting MIN6 cells and isolated rat islets, and this effect was
blocked in MIN6 cells by the EGFR inhibitor AG1478 or the mTOR inhibitor rapamycin. Coinfusion of either AG1478 or rapamycin
blocked the increase in FOXM1 signaling, β-cell proliferation, and β-cell mass and size in response to GLU+IL infusion in
6-month-old rats. We conclude that chronic nutrient excess promotes β-cell mass expansion via a pathway that involves EGFR
signaling, mTOR activation, and FOXM1-mediated cell proliferation.